Synthesis of tryptophane and intermediates therefor



UNITED STATES PATENT orricr.

SYNTHESIS OF TRYPTOPHANE AND INTEBMEDIATES THEREFOR Harold B. Snyder, Urbana, 111., and Curtis W. Smith, Berkeley, Oalii., minors to Merck & 330., Inc., Rahway, N. 3., a corporation of New ersey No Drawing. Application October 21, 1944,

- Serial No. 559,837

21 Claims. (Cl. 280-319) This invention relates generally to processes E l for producing dl-tryptophane, and particularly to e 1 a new process for preparing di-tryptophane from About 6.9 g. of sodium is powdered in approxisubstances not previously used as starting matemfltely 100 01? Xylene and most of the Xy rials, and to new substances as intermediates in e oved by decantation. To this p d said process. dium is added about 500 cc. of dioxane (distilled dl-Tryptophane ha been heretofore prepared from sodium) and about 68 g. of ethyl acetamidoby condensation of ind01e-3-aldehyde ith hymalonate, and the mixture is maintained at about dantoin or hippuric acid. It is now discovered 9 C. for 14 hours with agitation. To the resultaccording to the present invention that the synmg ligh y l Suspension is added 1 o thesis of dl-tryptophane i efiected by reacting gramine methlodide and the mixture is stirred quaternary substituted 3 aminomethyl-indole, f about 19 h u s a app y and for example, gramme methiodide, with acylamithen for about 3 hours at about 125 C. The redomalonic esters. suiting solution is cooled, causing precipitation of Regarding in certain of its broader aspects, the 15 yl a alcetamido-o-calbethoxy-fl-(341M016) novel process accordin to this invention compropionate (M. P. 158 C.) which is removed by prises condensation of alkali metal-derivatives of filtration and purified by Conventional methodsmonoacy1- and diacylamidomalonic ste with About 33.62 g. of the ester so prepared is heated quaternary ammonium salts of S-aminomethylunder reflux wit eof sodiu ydroxide i indole, hydrolysis of the esters of -acylamido-a- 20 192 cc. of water for about 4 hours. The resultin carboxy-fi-(Zl-indole)-propionic acid to the disolution is treated with activated carbon, filtered, carboxylic acids, conversion of the a-acylamidocooled, and acidified with hydrochloric acid while aC8.IbOXY-B-(3-ind0l6) -propionic acid to the retaining t p ure below C. The rea-acylamido-fi-(3-indo1e) -propionic acid, and sulting solution is retained thus cooled for about hydrolysis of the a-acylaJnido-fl-(3-indole)-pro- 2c 4 hours causing the separation of u-acetamidopionic acid thus formed to dl-tryptophane. The y-fid -p p1 d M.

reactions are indicated as follows: 144.5 C. with decomposition) which is removed /R C O 0 R1 /R| CHz-N-R R CH;- N NBOH 2 R MJJN l lh til 355* N l \RI N O OBI O O R: v

' C O O H l R: 011,-- N E cm-oncoon 22E cm-cncoon O I l heat. 0 i l; then H J 11TH,

\ 0 on N Ri Rr \N H H H di-tryptophane where R is alkyl, aryl, or aralkyl, R1 is alkyl, aryl, y filtration and purified by ry l ti n or aralkyl, R2 is hydrogen or acyl, R3 is acyl, or from aqueous methanol solution. R2 and R3 may be a dicarboxylic organic acid About 28 of the (3-indo1e)-propionic acid is heated under reflux radmal' X is halogen and M is an alkali forming with about 120 cc. of water for approximately 2 metal hours. The N-acetyltryptophane (M. P. 206 C.) The followmg examples illustrate methods of separates from the solution and can be recovered carrying out the present invention but it is to be by filtratio However in the production of understood that these examples are given by W y dl-tryptophane it is not necessary to isolate the of illustration and not of limitation. N-acetyltryptophane, and the hydrolysis of the Example 11 a 18.3 g. of ethyl phthalimidomalonate is added to 1.15 g. of powdered sodium in 75 cc. of N-butylether, and the mixture is heated with agitation at 120 C. for about 10 hours and then at 150 C. for about 4 hours. To this suspension is added about 17.4 g. oi gramine methiodide and the mixture is heated with agitation at approximately 105 C. for about 18 hours. The hot butyl other solution is then decanted from a red pasty mass and cooled causing precipitation 01' ethyl-a-phthalimido-acarbethoxy-fl-(3-indole) .propionate (M P. 177 C.) which is removed by filtration and purified by recrystallization from a mixture of benzene and ligroin.

About 2 g. of CthYI-a-DhthSl-lMldO-c-Ofltbethoxy-p-(S-indole) propionate is refluxed for about 5 hours with 1 g. of sodium hydroxide in cc. of water. The resulting solution is treated with activated carbon, filtered, cooled, acidified with about 4 cc.-of hydrochloric acid (conc.) and allowed to stand at about 5 C. for approximately 16 hours. The acidic solution is then decanted from the a-phthalimido-a-carboxy-p-(3-indole) propionic acid which separates as an oil, and the oil is refluxed for about ihours with 20 cc. 0! water. Then about 3 g. of sodium hydroxide is added and the solution is refluxed for about 22 hours. The resulting solution is treated with activated carbon, filtered, acidified with about 4.5 cc. of acetic acid (glacial) and cooled causing the separation of a mixture of phthalic acid and dl-tryptophane. The dl-tryptophane is separated from the phthalic acid by extraction of the precipitate with a solution of 5 cc. of hydrochloric acid (conc.) in cc. of water. This extract is then made neutral with ammonium hydroxide solution, slightly acidified with a small amount of acetic acid, and cooled causing precipitation of the dl-tryptophane (M. P. 275 C. with decomposition) which is removed by filtration.

Example II! T a solution of about 19.32 g. of sodium in 1000 cc. of absolute ethanol is added about 198 g. of ethyl acetamidomalonate and the mixture refiuxed for about V2 hour. To the resulting solution is added about 304 g. of gramine methiodide and the mixture refluxed for approximately 26 hours. The hot reaction mixture is then filtered, and the filtrate cooled causing precipitation of ethyl-o-acetamido-a-carbethoxy p (3-indole) propionate (M. P. 158159 C.) which is recovered by filtration and purified by conventional operations.

The ethyl-a-acetamido-o-carbethoxy-p-(3-indole) -propionate thus obtained is subsequently treated in accordance with the process of Example I to recover dl-tryptophane.

Example IV The process as described in Example I is repeated while maintaining a nitrogen atmosphere throughout the reactions. The yield is thereby increased.

Example V The process as described in Example 11 is repeated while maintaining a nitrogen atmosphere throughout the reactions; and an increased yield of dl-tryptophane is obtained.

The examples illustrate the reaction of the methiodides oi p-(dimethylaminomethyD-indole (gramine methiodide) with alkali metal derivatives of ethyl acetamidomalonate and ethyl phthalimidomalonate. It is to be understood however that other quaternary substituted (aminomethyl) -indole compounds such as e (diethyiaminomethyl) -indole ethiodide, p(di-phenyl-aminomethvD-indole methiodide, and p-(dibenzylaminomethyl) -indole methiodide and the like can be employed. In the condensation thereof with an alkali. metal derivative of an acylamidomalonic ester, the amine by-product is removed as a gas if low boiling as in the case of trimethylamine or triethylamine; or ii higher boiling. as in the case of diphenyl-N-methylamine or dibenzyl-N-methylamine. it is retained in the solvent and thus separated from the precipitated condensation product.

The process also proceeds in like manner when the alkali metal derivative of the monoacyl or diacylamino malonic ester contains other ester groups of other acyl radicals. Thus alkali metal derivatives of methyl acetamidomalonate, phenyl acetamidomalonate, benzyl acetamidomalonate and the like or corresponding esters of other monoacyl or diacyl amidomalonic acids such as formamidomalonic acid, benzamidomalonic acid,

phthalimidomalonic acid and the like can be employed.

The condensation products thus formed are methyl, phenyl. or benzyl esters of m-acetamidoa-carboxy-B-(S-indole) -propionic acid, a-iormamido-e-carboxys-(li-indole) -propionic acid, abenzamido-s-carboxy-p-(ii-indole) propionic acid. and a-phthalimido-a-carboxy-fl- (3-indole) propionic acid. These intermediate compounds are converted to dl-tryptophane by deesteriflcation, recarboxylation, and deacetylation in the manner previously described.

By the term acylamido" as employed in the following claims is meant: an amido'group of the class consisting of mono-acylamido and di-acylamido groups, including di-acylamido groups wherein the acyl substituents are linked by an alkyl or an aryl grouping. It is also to be understood that the esters referred to in the specification and claims are the di-esters.

Modifications may be made in carrying out the present invention without departing from the spirit and scope thereof and the invention is to be limited only by the appended claims.

What is claimed is:

1. The process that comprises reacting an indole compound having a p substituent of the formula CHa- R where R is selected from the class consisting of alkyl, aryl, and aralkyi groups, and X is a halogen, with a compound of the formula where R1 is selected from the class consisting of alkyl, aryl, and aralkyl groups. R: is selected from heating this compound in dilute aqueous alkali to hydrolyze the groups R1 and acidifying to form the corresponding dicarboxylic acid, heating said' dicarboxylic acid with water to form the corresponding monocarboxylic acid, deacylating said monocarboxylic acid by heating in aqueous alkali, and acidifying the resulting alkaline solution to precipitate dl-tryptophane.

2. The process that comprises reacting an indole compound having a n substituent of the formula where R is selected from the class consisting of alkyl, aryl, and aralkyl groups, and X is halogen, with a compound of the formula COORl where R1 is selected from the class consisting of alkyl, aryl, and aralkyl groups. R2 is selected from the class consisting of hydrogen and acyl groups, R: is an acyl group, and M is an alkali metal to form an indole compound having a B substituent of the formula COOR1 R: CH2--CN/ COORi 3. The process that comprises reacting an indole compound having a ,8 substituent of the formula where R is selected from the class consisting of alkyl, aryl, and aralkyl groups, and X is halogen, with a compound of the formula CUOR COORi where R1 is selected from the class consisting of alkyl, aryl, and aralkyl groups, R2 is selected from the class consisting of hydrogen and acyl groups, R: is an acyl group. and M is an alkali metal, in

6 a nitrogen atmosphere, to form an indole compound having a 3 substituent of the formula COORi RI -CHr- N/ com 4. The process that comprises reacting an indole compound having a d substltuent of the formula 3 -cH,-1 1- -a x n where R is selected from the class consisting oi alkyl, aryl, and araikyl groups, and X is halogen, with a compound of the formula where R1 is selected from the class consisting of alkyl, aryl, and aralkyl groups, R: is selected from the class consisting of hydrogen and acyl groups, R: is an acyl group, and M is an alkali metal, in the presence of a non-reactive organic liquid which is a solvent for the starting materials to form an indole compound having a p substituent of the formula R: -CHr-CN COORI 5. The process that comprises reacting an indole compound having a p substituent of the formula R -CH1NR where R is selected from the class consisting of alkyl, aryl, and aralkyl groups, and X is halogen, with a compound of the formula COORi where R1 is selected from the class consisting of alkyl, aryl, and aralkyl groups, R2 is selected from the class consisting of hydrogen and acyl groups, R: is an acyl group. and M is an alkali metal, in the presence of a non-reactive organic liquid which is a solvent for the starting material while maintaining a nitrogen atmosphere, to form an indole compound having a a substituent of the formula 6. The process that comprises hydrolysing an indole compound having a p substituent of the formula R: -CHr- -N 00034 i N/Rl CH:

l R: 00R

where R1 is selected from the class consisting of alkyl, aryl. and aralkyl groups. R: is selected from the class consisting of hydrogen and acyl groups, and R: is an acyl group, to the corresponding dicarboxyllc acid, heating said dicarboxylic acid with water to remove one carboxy group, heating the monocarboxylic acid thus obtained in aqueous alkali, acidifying the resulting alkaline solution to precipitate dl-tryptophane. and conducting said reactions in a nitrogen atmosphere.

8. The process that comprises heating an ester of an c-acylamido-a-carboxy-fi- (3-indole) -prcpicnic acid in dilute aqueous alkali and acidifying to form the corresponding dicarboxylic acid.

9. The process that comprises heating an aacylamido-a-carboxy ,8 (3 -indo1e) propionic acid in water to form the corresponding c-acylamido-fl-(3-indole) -proplonic acid.

10. The process that comprises heating an o:- acylamido-p-(3-indole) -propionic acid in aqueous alkali, and acidifying the resulting alkaline solution to precipitate dl-tryptophane.

lL-The process that comprises reacting the methiodide of 3-dimethylaminomethyl indole with the sodium derivative of ethyl acetamidomalonate to form ethyl a-aoetamido-a-carbethoxy-p- (3-indole) -propionate.

12. The process that comprises reacting the methlodide of 3-dimethyiamlnomethyl indole with the sodium derivative of ethyl acetamidcmaionate to form ethyl a-acetamido-a-carbethoxy-p-(3-indole) -proplonate. heating this substancein dilute aqueous alkali and acidifying to iorm a-acetamido-a-carboxy-p-(S-indole)-propicnic acid, heating the latter in water to produce dl-N-acetyltryptophane. and heating the same in aqueous alkali. and acidifying the resulting alkaline solution to precipitate dl-tryptophane.

13. The process that comprises heating ethyl oracetamido-a-carbethoxy fi-(ii indole) propichate in dilute aqueous alkali and acidifying to form a-acetamido-a-carboxy-p-(3-indole) propionic acid. decarboxylating the latter by heating in water. heating the dl-N-acetyltryptophane thus formed with aqueous alkali and acidifying the resulting alkaline solution to precipitate dl-tryptophone.

14. The process that comprises reacting the methiodlde of 3-dimethylaminomethyl indole with the sodium derivative of ethyl phthallmidomalonate to form ethyl-a-phthallmido-a-carbethoxy-p-(3-lndole) -propionate, heating this substance in dilute aqueous alkali and acidifyin to form a-phthalimido-a-carboxy-p-(ll-indole) -propicnic acid, heating the latter in water to produce N-phthalimidotryptophane, and heating the same in aqueous alkali. and acidifying the resulting aikaline solution to precipitate dl-tryptophane.

15. The process that comprises heating ethyl a-phthalimido-a-carbethoxy-fl-(3- indole) propionate in dilute aqueous alkali and acidifying to form a-phthaiimido-a-carboxy-p-(3-indole) -propicnic acid. decarboxylatlng the latter by heating in water, heating the N-phthalimidotryptophane thus formed with aqueous alkali and acidifying the resulting alkaline solution to precipitate d1- tryptophane.

16. A compound selected from the class consisting of a-acylarnido-a-carboxy-fi-(ii-indole)- propionic acids and esters thereof. dole) -proplonic acids.

17. Esters of a-acylamido-a-carboxy-fl-(3-indole) -propionic acids.

18. a-Acylamidoa carboxy p (3 indole)- propionic acids.

19. Ethyl a-acetamido-a carbethoxy p (3- indoie) -propicnate.

20. a-Acetamido-a carboxy p (3 indole) propionic acid.

21. s-Phthalimldo-a carboxy p (S-indole) propionic acid.

HAROLD R. SNYDER. CURTIS W. SMITH.

REFERENCES CITED The following references are of record in the file of this patent:

Albertson et al.: J. Am. Chem. Soc. (1944), vol. 66. case 500. 

